Microplastics Biodegradation by Estuarine and Landfill Microbiomes.

Plastic pollution poses a worldwide environmental challenge, affecting wildlife and human health. Assessing the biodegradation capabilities of natural microbiomes in environments contaminated with microplastics is crucial for mitigating the effects of plastic pollution. In this work, we evaluated the potential of landfill leachate (LL) and estuarine sediments (ES) to biodegrade polyethylene (PE), polyethylene terephthalate (PET), and polycaprolactone (PCL), under aerobic, anaerobic, thermophilic, and mesophilic conditions. PCL underwent extensive aerobic biodegradation with LL (99 ± 7%) and ES (78 ± 3%) within 50-60 days. Under anaerobic conditions, LL degraded 87 ± 19% of PCL in 60 days, whereas ES showed minimal biodegradation (3 ± 0.3%). PE and PET showed no notable degradation. Metataxonomics results (16S rRNA sequencing) revealed the presence of highly abundant thermophilic microorganisms assigned to Coprothermobacter sp. (6.8% and 28% relative abundance in anaerobic and aerobic incubations, respectively). Coprothermobacter spp. contain genes encoding two enzymes, an esterase and a thermostable monoacylglycerol lipase, that can potentially catalyze PCL hydrolysis. These results suggest that Coprothermobacter sp. may be pivotal in landfill leachate microbiomes for thermophilic PCL biodegradation across varying conditions. The anaerobic microbial community was dominated by hydrogenotrophic methanogens assigned to Methanothermobacter sp. (21%), pointing at possible syntrophic interactions with Coprothermobacter sp. (a H2-producer) during PCL biodegradation. In the aerobic experiments, fungi dominated the eukaryotic microbial community (e.g., Exophiala (41%), Penicillium (17%), and Mucor (18%)), suggesting that aerobic PCL biodegradation by LL involves collaboration between fungi and bacteria. Our findings bring insights on the microbial communities and microbial interactions mediating plastic biodegradation, offering valuable perspectives for plastic pollution mitigation.

Epilactose as a Promising Butyrate-Promoter Prebiotic via Microbiota Modulation.

Epilactose is a disaccharide composed of galactose and mannose, and it is currently considered an "under development" prebiotic. In this study, we described the prebiotic potential of epilactose by in vitro fermentation using human fecal inocula from individuals following a Mediterranean diet (DM) or a Vegan diet (DV). The prebiotic effect of epilactose was also compared with lactulose and raffinose, and interesting correlations were established between metabolites and microbiota modulation. The production of several metabolites (lactate, short-chain fatty acids, and gases) confirmed the prebiotic properties of epilactose. For both donors, the microbiota analysis showed that epilactose significantly stimulated the butyrate-producing bacteria, suggesting that its prebiotic effect could be independent of the donor diet. Butyrate is one of the current golden metabolites due to its benefits for the gut and systemic health. In the presence of epilactose, the production of butyrate was 70- and 63-fold higher for the DM donor, when compared to lactulose and raffinose, respectively. For the DV donor, an increase of 29- and 89-fold in the butyrate production was obtained when compared to lactulose and raffinose, respectively. In conclusion, this study suggests that epilactose holds potential functional properties for human health, especially towards the modulation of butyrate-producing strains.

A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange-mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.

From images to insights: a neuroradiologist's practical guide on white matter fiber tract anatomy and DTI patterns for pre-surgical planning.

INTRODUCTION: Diffusion tensor imaging (DTI) is a valuable non-invasive imaging modality for mapping white matter tracts and assessing microstructural integrity, and can be used as a "biomarker" in diagnosis, differentiation, and therapeutic monitoring. Although it has gained clinical importance as a marker of neuropathology, limitations in its interpretation underscore the need for caution. METHODS: This review provides an overview of the principles and clinical applicability of DTI. We focus on major white matter fiber bundles, detailing their normal anatomy and pathological DTI patterns, with emphasis on tracts routinely requested in our neurosurgical department in the preoperative context (uncinate fasciculus, arcuate fasciculus, pyramidal pathway, optic radiation, and dentatorubrothalamic tract). RESULTS: We guide neuroradiologists and neurosurgeons in defining volumes of interest for mapping individual tracts and demonstrating their 3D reconstructions. The intricate trajectories of white matter tracts pose a challenge for accurate fiber orientation recording, with each bundle exhibiting specific characteristics. Tracts adjacent to brain lesions are categorized as displaced, edematous, infiltrated, or disrupted, illustrated with clinical cases of brain neoplasms. To improve structured reporting, we propose a checklist of topics for inclusion in imaging evaluations and MRI reports. CONCLUSION: DTI is emerging as a powerful tool for assessing microstructural changes in brain disorders, despite some challenges in standardization and interpretation. This review serves an educational purpose by providing guidance for fiber monitoring and interpretation of pathological patterns observed in clinical cases, highlighting the importance and potential pitfalls of DTI in neuroradiology and surgical planning.

Impact of blood salvage therapy during oncologic liver surgeries on allogenic transfusion events, survival, and recurrence: an ambidirectional cohort study.

INTRODUCTION: The use of autologous blood transfusions in oncologic surgeries is somewhat controversial due to the potential risk of disease dissemination through the salvage process. On the other hand, autologous blood transfusion can prevent the potential negative effects of allogenic blood transfusions and reduce use of valuable resources. METHODS: This study included 106 adult patients who underwent oncologic liver surgery at our institution between December 2015 and June 2019. The patients were divided into two groups: the Cell Saver group (operated between January 2018 and June 2019) and the control group (operated between December 2015 and December 2017). The Cell Saver device was present in the operating room for the Cell Saver group, and blood was retransfused if a certain amount of blood loss occurred. Data analysis focused on outcomes such as blood transfusion requirements, overall survival, recurrence-free survival, hemoglobin levels, hospital stay, and complications. Patient records provided relevant information on demographics, surgery details, pathology, and outcomes for both groups. RESULTS: Autologous blood transfusion was found to reduce the amount of blood units needed (4.0 units (control group) versus 0.4 units (Cell Saver group) P =0.029. Kaplan-Meier curves showed no difference for both overall survival 471.6 days (Cell Saver group) versus 468.3 days (control group) ( P =0.219) and 488.9 days (Cell Saver group) versus 487.2 days (control group) ( P =0.993) and disease-free survival ( P =0.553) and ( P =0.735) for primary hepatic tumors and hepatic metastasis respectively between the Cell Saver and control groups. Overall survival regardless of the type of tumor was similar to the control group (485.4 days vs. 481.9 days) ( P =0.503). Survival was significantly lower for minor hepatectomies (516.0 days vs. 517.4 days) ( P =0.050) in the Cell Saver group, major hepatectomies showed no difference in overall survival (470.2 days vs. 466.4 days) ( P =0.868). No impact on disease recurrence was found between patients who received autologous blood transfusions versus those who did not. CONCLUSION: The use of Cell Saver should not be avoided in oncologic surgeries of the liver. Use of Cell Saver for major hepatectomies might be more beneficial as OS was significantly lower for the Cell Saver group for patients who underwent minor hepactomies. Further research is needed to explain this conflicting result. Nonetheless, the use of Cell Saver in autologous blood transfusions can reduce the use of valuable resources and the risks associated with allogenic blood transfusions.

Translation initiation factor eIF1A rescues hygromycin B sensitivity caused by deleting the carboxy-terminal tail in the GPN-loop GTPase Npa3.

The essential yeast protein GPN-loop GTPase 1 (Npa3) plays a critical role in RNA polymerase II (RNAPII) assembly and subsequent nuclear import. We previously identified a synthetic lethal interaction between a mutant lacking the carboxy-terminal 106-amino acid tail of Npa3 (npa3ΔC) and a bud27Δ mutant. As the prefoldin-like Bud27 protein participates in ribosome biogenesis and translation, we hypothesized that Npa3 may also regulate these biological processes. We investigated this proposal by using Saccharomyces cerevisiae strains episomally expressing either wild-type Npa3 or hypomorphic mutants (Npa3ΔC, Npa3K16R, and Npa3G70A). The Npa3ΔC mutant fully supports RNAPII nuclear localization and activity. However, the Npa3K16R and Npa3G70A mutants only partially mediate RNAPII nuclear targeting and exhibit a higher reduction in Npa3 function. Cell proliferation in these strains displayed an increased sensitivity to protein synthesis inhibitors hygromycin B and geneticin/G418 (npa3G70A > npa3K16R > npa3ΔC > NPA3 cells) but not to transcriptional elongation inhibitors 6-azauracil, mycophenolic acid or 1,10-phenanthroline. In all three mutant strains, the increase in sensitivity to both aminoglycoside antibiotics was totally rescued by expressing NPA3. Protein synthesis, visualized by quantifying puromycin incorporation into nascent-polypeptide chains, was markedly more sensitive to hygromycin B inhibition in npa3ΔC, npa3K16R, and npa3G70A than NPA3 cells. Notably, high-copy expression of the TIF11 gene, that encodes the eukaryotic translation initiation factor 1A (eIF1A) protein, completely suppressed both phenotypes (of reduced basal cell growth and increased sensitivity to hygromycin B) in npa3ΔC cells but not npa3K16R or npa3G70A cells. We conclude that Npa3 plays a critical RNAPII-independent and previously unrecognized role in translation initiation.

Nucleocytoplasmic shuttling of the GPN-loop GTPase Gpn3 is regulated by serum and cell density in MCF-12A mammary cells.

The best-known function of the essential GPN-loop GTPase Gpn3 is to contribute to RNA polymerase II assembly, a prerequisite for its nuclear targeting. Although this process occurs in the cytoplasm, we have previously shown that Gpn3 enters the cell nucleus before being polyubiquitinated. Here, we show that inhibiting Crm1-mediated nuclear export with leptomycin B, or the proteasome with MG132, caused the nuclear accumulation of recombinant and endogenous Gpn3 in MCF-12A cells. When added simultaneously, leptomycin B and MG132 had an additive effect. Analysis of Gpn3 primary sequence revealed the presence of at least five nuclear export sequence (NES) motifs, with some having a higher exposure to the solvent in the GTP-bound than GDP-bound state in a Gpn3 structural model. Inactivation of any of these NESes led to some degree of Gpn3 nuclear accumulation, although mutating NES1 or NES3 had the more robust effect. MCF-12A cells expressing exclusively a NES-deficient version of Gpn3R-Flag proliferated slower than cells expressing Gpn3R-Flag wt, indicating that nuclear export is important for Gpn3 function. Next, we searched for physiological conditions regulating Gpn3 nucleocytoplasmic shuttling. Interestingly, whereas Gpn3R-Flag was both nuclear and cytoplasmic in low-density growing MCF-12A cells, it was exclusively cytoplasmic in high-density areas. Furthermore, Gpn3R-Flag was cytoplasmic, mostly perinuclear, in sparse but starved MCF-12A cells, and serum-stimulation caused a rapid, although transient, Gpn3R-Flag nuclear accumulation. We conclude that Gpn3 nucleocytoplasmic shuttling is regulated by cell density and growth factors, and propose that Gpn3 has an unknown nuclear function positively linked to cell growth and/or proliferation.

Development of Neural Mechanisms Underlying Threat Processing: Associations With Childhood Social Reticence and Adolescent Anxiety.

Background: Social reticence in early childhood is characterized by shy and anxiously avoidant behavior, and it confers risk for pediatric anxiety disorders later in development. Aberrant threat processing may play a critical role in this association between early reticent behavior and later psychopathology. The goal of this longitudinal study is to characterize developmental trajectories of neural mechanisms underlying threat processing and relate these trajectories to associations between early-childhood social reticence and adolescent anxiety. Methods: In this 16-year longitudinal study, social reticence was assessed from 2 to 7 years of age; anxiety symptoms and neural mechanisms during the dot-probe task were assessed at 10, 13, and 16 years of age. The sample included 144 participants: 71 children provided data at age 10 (43 girls, meanage = 10.62), 85 at age 13 (46 girls, meanage = 13.25), and 74 at age 16 (36 girls, meanage = 16.27). Results: A significant interaction manifested among social reticence, anxiety symptoms, and time, on functional connectivity between the left amygdala and the left dorsolateral prefrontal cortex, voxelwise p < .001, clusterwise familywise error p < .05. Children with high social reticence showed a negative association between amygdala-dorsolateral prefrontal cortex connectivity and anxiety symptoms with age, compared to children with low social reticence, suggesting distinct neurodevelopmental pathways to anxiety. Conclusions: These findings were present across all conditions, suggesting task-general effects in potential threat processing. Additionally, the timing of these neurodevelopmental pathways differed for children with high versus low social reticence, which could affect the timing of effective preventive interventions.

A Nutrigenetic Strategy for Reducing Blood Lipids and Low-Grade Inflammation in Adults with Obesity and Overweight.

The pathogenesis of obesity and dyslipidemia involves genetic factors, such as polymorphisms related to lipid metabolism alterations predisposing their development. This study aimed to evaluate the effect of a nutrigenetic intervention on the blood lipid levels, body composition, and inflammation markers of adults with obesity and overweight. Eleven genetic variants associated with dyslipidemias in Mexicans were selected, and specific nutrigenetic recommendations for these polymorphisms were found. One hundred and one adults were recruited and assigned to follow either a standard or nutrigenetic diet for eight weeks. Anthropometric, biochemical, body composition, and inflammation markers were evaluated through standardized methods. Weighted genetic risk scores (wGRSs) were computed using the study polymorphisms. After intervention, both diets significantly decreased the anthropometric parameters and body composition (p < 0.05). Only the nutrigenetic diet group showed significant reductions in VLDL-c (p = 0.001), triglycerides (p = 0.002), TG:HDL (p = 0.002), IL-6 (p = 0.002), and TNF-α (p = 0.04). wGRSs had a high impact on the ΔTGs and ΔVLDL-c of both groups (standard diet: ΔTGs: Adj R2 = 0.69, p = 0.03; ΔVLDL-c: Adj R2 = 0.71, p = 0.02; nutrigenetic diet: ΔTGs: Adj R2 = 0.49, p = 0.03 and ΔVLDL-c: R2 = 0.29, p = 0.04). This nutrigenetic intervention improved lipid abnormalities in patients with excessive body weight. Hence, nutrigenetic strategies could be coadjuvant tools and enhance the standard dietary treatment for cardiometabolic diseases.

Extrapyramidal Side Effects with Chronic Atypical Antipsychotic Can Be Predicted by Labeling Pattern of FosB and phosphoThr34-DARPP-32 in Nucleus Accumbens.

Extrapyramidal side effects (EPS) can be induced by neuroleptics that regulate the expression of transcription factor FosB and dopaminergic mediator DARPP-32 in the striatum. However, the long-term neurobiological changes in striatal projection neurons resulting from a cumulative dosage of typical and atypical antipsychotics are poorly understood. The present study aimed to determine the differential and long-lasting changes in FosB distribution and DARPP-32 phosphorylation in the striatum and nucleus accumbens (NAc) associated with chronic antipsychotic-induced EPS. Male C57Bl/6J mice received daily injections of Olanzapine (Olz, 15 mg/kg), Clozapine (Clz, 20 mg/kg), or Haloperidol (Hal, 1 mg/kg), for a period of 11 weeks with a 4-day withdrawal period before the last dosage. Catalepsy for detection of EPS, along with open-field and rotarod tests, were assessed as behavioral correlates of motor responses. Additionally, FosB and phosphorylated-DARPP-32 immunohistochemistry were examined in striatal regions after treatment. All antipsychotics produced catalepsy and reduced open-field exploration, such as impaired rota-rod performance after Olz and Hal. The washout period was critical for Clz-induced side effects reduction. Both Olz and Clz increased FosB in NAc Shell-region, and phosphoThr34-DARPP-32 in NAc. Only Clz reduced phosphoThr75-DARPP-32 in the dorsal striatum and showed FosB/phosphoThr34-Darpp-32-ir in the NAc Core region. This study provides evidence that atypical antipsychotics such as Olz and Clz also give rise to EPS effects frequently associated with a cumulative dosage of typical neuroleptics such as Hal. Nevertheless, FosB/phosphoThr34-Darpp-32-ir in the NAc Core region is associated with hypokinetic movements inhibition.

Closing the loop between horizon scanning and health technology assessment - an overview of topics submitted for appraisal in England.

OBJECTIVES: Horizon scanning for health technology appraisal (HTA) in England involves topic notification to the National Institute for Health and Care Excellence (NICE) via technology briefings. This activity is undertaken by the Innovation Observatory with submission timelines designed to ensure that HTA decisions align with regulatory approval time. In this paper, we aimed to track and assess the progression and current status of the topics notified for HTA and provide a descriptive analysis of these topics. METHODS: Technology briefings were mapped from submission to NICE technology appraisal/highly specialized technologies recommendations from April 2017 until October 2021. This was done using a combination of searches on Google and NICE website, searching a downloadable spreadsheet containing NICE topic selection decisions, and querying NICE Topic Selection team. Analysis was undertaken regarding type of indications and interventions of submitted topics and published guidance. RESULTS: Six-hundred and ninety-three topics entered the NICE scoping process, of which 94 percent were prioritized. As of November 2021, approximately 39 percent of prioritized topics were in scoping/in progress, 31 percent were proposed/completed, 20 percent were suspended/terminated, and 4 percent were referred back to Innovation Observatory (IO) for further monitoring. CONCLUSIONS: Our work demonstrates that horizon scanning for HTA is a complex and time-intensive process. Timelines and progress through HTA is challenging due to the growing number of innovative medicines, significant uncertainties, and limited transparency in clinical development and regulatory pathways. A better understanding of clinical trials and regulatory requirements may help eliminate some of this uncertainty and improve timely HTA.

Distinct neurocognitive fingerprints reflect differential associations with risky and impulsive behavior in a neurotypical sample.

Engagement in risky and impulsive behavior has long been associated with deficits in neurocognition. However, we have a limited understanding of how multiple subfunctions of neurocognition co-occur within individuals and which combinations of neurocognitive subfunctions are most relevant for risky and impulsive behavior. Using the neurotypical Nathan Kline Institute Rockland Sample (N = 673), we applied a Bayesian latent feature learning model-the Indian Buffet Process-to identify nuanced, individual-specific profiles of multiple neurocognitive subfunctions and examine their relationship to risky and impulsive behavior. All features were within a relatively normative range of neurocognition; however, there was subtle variability related to risky and impulsive behaviors. The relatively overall poorer neurocognition feature correlated with greater affective impulsivity and substance use patterns/problems. The poorer episodic memory and emotion feature correlated with greater trait externalizing and sensation-seeking. The poorer attention feature correlated with increased trait externalizing and negative urgency but decreased positive urgency and substance use. Finally, the average or mixed features negatively correlated with various risky and impulsive behaviors. Estimating nuanced patterns of co-occurring neurocognitive functions can inform our understanding of a continuum of risky and impulsive behaviors.

Is Increasing Parity Associated with Adverse Perinatal Outcomes in Dichorionic Twin Gestations?

OBJECTIVE: Dichorionic twins have increased risk of preterm birth and hypertensive disorders of pregnancy. Grand multiparity may be associated with adverse perinatal outcomes in singleton pregnancies, although the effect of increasing parity in twins is unclear. This study aimed to elucidate whether grand multiparity leads to adverse outcomes in dichorionic twins compared with multiparity and nulliparity. STUDY DESIGN: This was a retrospective review of dichorionic twins at a single institution between January 2008 and December 2019 comparing pregnancy outcomes among grand multiparity, multiparity, and nulliparity. Primary outcome was preterm birth less than 37 weeks. Multivariable regression controlled for differing demographics, prior preterm birth, use of reproductive technologies, and hypertensive disorders of pregnancy. Chi square and Fisher's exact were used for categorical variables and Kruskal-Wallis was used for continuous variables. RESULTS: A total of 843 (60.3%) pregnancies were nulliparous, 499 (35.7%) multiparous, and 57(4.1%) grand multiparous. Univariate analysis indicated that multiparous women had lower incidence of preterm birth less than 37, 34, and 32 weeks (57 vs. 51%, p = 0.04; 19.2 vs. 14.0%, p = 0.02; 9.6 vs. 5.6%, p = 0.01) and that grand multiparous women had lower incidence of preterm birth less than 34 weeks (19.2 vs. 5.3%, p = 0.008) compared with nulliparous women. Multivariable regression confirmed multiparous women had lower odds of preterm birth less than 34 and 32 weeks compared with nulliparous women (<34 wk: odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.49-0.97, p = 0.03; <32 wk: OR = 0.48, 95% CI = 0.29-0.79, p = 0.004) and that multiparous women (OR = 0.57, 95% CI = 0.42-0.77, p = 0.0002) and grand multiparous women (OR = 0.23, 95% CI = 0.08-0.68, p = 0.0074) had lower incidence of hypertensive disorders of pregnancy when compared with nulliparous women. CONCLUSION: Grand multiparity is not associated with adverse perinatal outcomes compared with nulliparity or multiparity in dichorionic twins. Increasing parity may protect against incidence of preterm birth and hypertensive disorders of pregnancy even among grand multiparous women. KEY POINTS: · Incidence of preterm birth may decrease with increasing parity in twins.. · Hypertensive disorders of pregnancy may decrease with increasing parity in twins.. · Grand multiparity is not associated with adverse perinatal outcomes in twins..

Pre-Heart Failure Longitudinal Change in a Hispanic/Latino Population-Based Study: Insights From the Echocardiographic Study of Latinos.

BACKGROUND: Pre-heart failure (pre-HF) is an entity known to progress to symptomatic heart failure (HF). OBJECTIVES: This study aimed to characterize pre-HF prevalence and incidence among Hispanics/Latinos. METHODS: The Echo-SOL (Echocardiographic Study of Latinos) assessed cardiac parameters on 1,643 Hispanics/Latinos at baseline and 4.3 years later. Prevalent pre-HF was defined as the presence of any abnormal cardiac parameter (left ventricular [LV] ejection fraction <50%; absolute global longitudinal strain <15%; grade 1 or more diastolic dysfunction; LV mass index >115 g/m2 for men, >95 g/m2 for women; or relative wall thickness >0.42). Incident pre-HF was defined among those without pre-HF at baseline. Sampling weights and survey statistics were used. RESULTS: Among this study population (mean age: 56.4 years; 56% female), HF risk factors, including prevalence of hypertension and diabetes, worsened during follow-up. Significant worsening of all cardiac parameters (except LV ejection fraction) was evidenced from baseline to follow-up (all P < 0.01). Overall, the prevalence of pre-HF was 66.7% at baseline and the incidence of pre-HF during follow-up was 66.3%. Prevalent and incident pre-HF were seen more with increasing baseline HF risk factor burden as well as with older age. In addition, increasing the number of HF risk factors increased the risk of prevalence of pre-HF and incidence of pre-HF (adjusted OR: 1.36 [95% CI: 1.16-1.58], and adjusted OR: 1.29 [95% CI: 1.00-1.68], respectively). Prevalent pre-HF was associated with incident clinical HF (HR: 10.9 [95% CI: 2.1-56.3]). CONCLUSIONS: Hispanics/Latinos exhibited significant worsening of pre-HF characteristics over time. Prevalence and incidence of pre-HF are high and are associated with increasing HF risk factor burden and with incidence of cardiac events.

In Vitro Gastrointestinal Digestion Affects the Bioaccessibility of Bioactive Compounds in Hibiscus sabdariffa Beverages.

Hibiscus sabdariffa possess great versatility to be used as an ingredient for a whole range of products with natural-based ingredients, which are growing in popularity due to the health benefits of bioactive compounds (BC). Therefore, the objective of this study was to characterize the BC content in Hibiscus beverages and to evaluate their in vitro bioaccessibility. Results showed significant differences (p < 0.05) in the total contents of BC prior to the in vitro intestinal digestion. Hibiscus acid was the most abundant compound identified. Thirty-five compounds were identified in the Hibiscus beverage at the initial stage, while a maximum of 15 compounds were quantified in the different fractions of gastrointestinal digestion. After digestion, significant differences were found compared with the initial content of BC. That phenolic acids were the less bioaccessible group, while flavonoids were the most diverse. Principal components analysis showed different clusters and changes in the profiles of BC present at the initial stage and those bioaccessible, showing that intestinal digestion significantly affects the BC profile of the beverage.

Fear-potentiated startle reveals diminished threat extinction in pathological anxiety.

BACKGROUND: Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. METHODS: Youths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. RESULTS: Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. CONCLUSION: ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

A low-cost, paper-based hybrid capture assay to detect high-risk HPV DNA for cervical cancer screening in low-resource settings.

Cervical cancer is a leading cause of cancer death for women in low-resource settings. The World Health Organization recommends that cervical cancer screening programs incorporate HPV DNA testing, but available tests are expensive, require laboratory infrastructure, and cannot be performed at the point-of-care. We developed a two-dimensional paper network (2DPN), hybrid-capture, signal amplification assay and a point-of-care sample preparation protocol to detect high-risk HPV DNA from exfoliated cervical cells within an hour. The test does not require expensive equipment and has an estimated cost of <$3 per test without the need for batching. We evaluated performance of the paper HPV DNA assay with short synthetic and genomic HPV DNA targets, HPV positive and negative cellular samples, and two sets of clinical samples. The first set of clinical samples consisted of 16 biobanked, provider-collected cervical samples from a study in El Salvador previously tested with careHPV and subsequently tested in a controlled laboratory environment. The paper HPV DNA test correctly identified eight of eight HPV-negative clinical samples and seven of eight HPV-positive clinical samples. We then performed a field evaluation of the paper HPV DNA test in a hospital laboratory in Mozambique. Cellular controls generated expected results throughout field testing with fully lyophilized sample preparation and 2DPN reagents. When evaluated with 16 residual self-collected cervicovaginal samples previously tested by the GeneXpert HPV assay ("Xpert"), the accuracy of the HPV DNA paper test in the field was reduced compared to testing in the controlled laboratory environment, with positive results obtained for all eight HPV-positive samples as well as seven of eight HPV-negative samples. Further evaluation showed reduction in performance was likely due in part to increased concentration of exfoliated cells in the self-collected clinical samples from Mozambique compared with provider-collected samples from El Salvador. Finally, a formal usability assessment was conducted with users in El Salvador and Mozambique; the assay was rated as acceptable to perform after minimal training. With additional optimization for higher cell concentrations and inclusion of an internal cellular control, the paper HPV DNA assay offers promise as a low-cost, point-of-care cervical cancer screening test in low-resource settings.

Bioaccessibility of phenolic compounds in Psidium guajava L. varieties and P. friedrichsthalianum Nied. after gastrointestinal digestion.

Psidium guajava L. and Psidium friedrichsthalianum Nied are part of the Psidium species native to America. Nowadays, it is essential to study the phenolic compound (PC) profile and their changes during digestion and the fractions available for absorption. This study aimed to characterize the PC profile in some Psidium species and their bioaccessibility (BA). Fifty-seven compounds were identified, and forty-six belonged to ten different phenolic classes. PC profiles showed significant differences between the species and the intestinal fraction P. friedrichsthalianum Nied. showed the highest PC content, although it mostly belonged to non-extractable polyphenols. This leads to the lowest BA (37%); P. guajava L. 'Morada' showed the highest (47%). Hydroxycinnamic acids were the most stable PC after gastrointestinal digestion. This study showed relevant differences in the PC content and profile of different Psidium species and changes between the PC in the original matrix and those released in the different stages of gastrointestinal digestion.

Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80.

Breast cancer cells must avoid intrinsic and extrinsic cell death to relapse following chemotherapy. Entering senescence enables survival from mitotic catastrophe, apoptosis and nutrient deprivation, but mechanisms of immune evasion are poorly understood. Here we show that breast tumors surviving chemotherapy activate complex programs of immune modulation. Characterization of residual disease revealed distinct tumor cell populations. The first population was characterized by interferon response genes, typified by Cd274, whose expression required chemotherapy to enhance chromatin accessibility, enabling recruitment of IRF1 transcription factor. A second population was characterized by p53 signaling, typified by CD80 expression. Treating mammary tumors with chemotherapy followed by targeting the PD-L1 and/or CD80 axes resulted in marked accumulation of T cells and improved response; however, even combination strategies failed to fully eradicate tumors in the majority of cases. Our findings reveal the challenge of eliminating residual disease populated by senescent cells expressing redundant immune inhibitory pathways and highlight the need for rational immune targeting strategies.

Gut metabolites produced during in vitro colonic fermentation of the indigestible fraction of a maize-based traditional Mexican fermented beverage, Tejuino.

Tejuino, is a Mexican fermented beverage prepared by germination-fermentation or nixtamalization-fermentation (artisanal and commercial mode respectively) of maize. The aim of this study was to evaluate the gut metabolites, volatile, and phenolic compounds (PC) produced by the indigestible fraction (IF) of Tejuino during an in vitro colonic fermentation. Twenty-six PC in the IF were identified; the hydroxycinnamic acids (30-40 %) were the most abundant. In the IF of Tejuino pyrogallol, and urolithins were identified. Some of the representative PC of maize as maysin derivatives (apimaysin and 3-methoxymaysin) (flavonoids). The quantification of acetic and butyric acid become notable after 6 h of the colonic fermentation of IF of Tejuino. Ninety-seven volatile compounds were found, and the PCA shows the predominant compounds as short chain fatty acids, esters of organic acids and indole derivatives. These results suggest that Tejuino could be an important source of metabolites with high biological value.